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Novel CAR T-Cell Therapy Shows Promise in Relapsed or Refractory Multiple Myeloma

Cellular therapy is becoming an attractive option for heavily pretreated patients with relapsed or refractory multiple myeloma. According to data presented at the ASCO 2020 virtual annual meeting, 2 chimeric antigen receptor (CAR) T-cell drugs have generated impressive rates of response that are sustainable.

In the pivotal KarMMa study, idecabtagene vicleucel (ide-cel) demonstrated frequent, deep, and durable responses in patients with heavily pretreated relapsed or refractory multiple myeloma, with overall response and complete response rates of 73% and 33%, respectively.

In a phase 1/2 trial, orvacabtagene autoleucel (orva-cel) also was very active in similarly heavily pretreated patients with relapsed or refractory multiple myeloma. The overall response rate (ORR) with orva-cel was 92%, including 68% of patients with a very good partial response or better.

The investigators of the studies called the results “highly encouraging” and said that both approaches represent potential new treatment options for patients with relapsed or refractory multiple myeloma, for whom there is no clear standard of care.

Idecabtagene Vicleucel

According to Nikhil C. Munshi, MD, Director of Basic and Correlative Science, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Boston, MA, for patients who have been exposed to a triple-drug regimen (ie, proteasome inhibitor, immunomodulatory drug, and monoclonal antibody) and have relapsed or refractory multiple myeloma, the prognosis is especially poor, with a median progression-free survival (PFS) of only 3 to 4 months.

Ide-cel is a B-cell maturation antigen (BCMA)-targeted CAR T-cell therapy that has shown promising tolerability and efficacy in patients with relapsed or refractory multiple myeloma. An early phase 1 study demonstrated an ORR of 85%, with a 10.9-month duration of response and a tolerable toxicity profile, said Dr Munshi.

For this pivotal phase 2 study, patients with relapsed or refractory multiple myeloma who had received ≥3 lines of therapy, including immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies, were eligible for enrollment. Patients also had to have disease refractory to the last line of therapy. Of the 140 patients enrolled in the study, 128 received ide-cel.

“Both primary and secondary end points were met, with an overall response of 73% and complete response of 33%,” he pointed out. “At the target dose of 450 million cells, the overall response was 82%, and 39% of patients had a complete response.”

The median time to first response was 1 month, and the median time to complete response was 2.8 months. The median follow-up was 13.3 months across all the dose levels.

The responses were deep too, said Dr Munshi, adding that 26% of patients were negative for minimal residual disease (MRD), and at the target dose, nearly 50% of the patients were MRD-negative.

“Clinical meaningful efficacy was observed across various subgroups,” he said. “Responses occurred irrespective of age, high-risk cytogenetics, tumor burden, BCMA expression, and extramedullary disease.”

At the target dose level, the median duration of response was 11.3 months, and among patients achieving a complete response, the duration of response improved to 19 months.

Similarly, the median PFS increased with the depth of response, from 12 months in the overall patient population to 20 months in patients achieving a complete response.

Finally, the safety data showed manageable toxicities. At the target dose level, 96% of patients had cytokine release syndrome (CRS); however, most of these events were grade 1 or 2. Dr Munshi noted that less than 6% of patients had grade ≥3 CRS at target dose levels, and neurotoxicity was low-grade and of limited extent.

Other significant adverse events involved cytopenia, with 91% and 63% of patients having neutropenia and thrombocytopenia, respectively. Infections were also observed in 69% of patients and were not dose-related. Of note, he said, there were 5 deaths overall within 8 weeks of ide-cel infusion, including 2 patients who died after myeloma progression and 3 died from adverse events.

“Overall, ide-cel provides an attractive and excellent option for treatment of triple class–exposed multiple myeloma,” Dr Munshi concluded.

Orvacabtagene Autoleucel

Sham Mailankody, MBBS, Medical Oncologist, Myeloma Service, Memorial Sloan Kettering Cancer Center, New York City, reported data from a phase 1/2 trial of orva-cel, a BCMA-directed CAR T-cell therapy for patients with heavily pretreated relapsed or refractory multiple myeloma.

“Orva-cel was highly active, with an overall response rate of 92% and a very good partial response or better in 68% of patients across the 3 highest dose levels tested,” said Dr Mailankody.

Robust expansion of CAR T-cells was observed at the 3 highest dose levels, and 84% of the evaluable responding patients were also MRD-negative. Responses were observed even in patients with the highest baseline levels of soluble BCMA, he reported.

Finally, the safety profile of orva-cel was encouraging at all dose levels, said Dr Mailankody, with low incidence of grade ≥3 CRS and neurologic events.

The study is continuing to enroll patients with relapsed or refractory multiple myeloma at the recommended dose (600 × 106 CAR T-cells) and includes a separate cohort for patients whose disease progressed after BCMA-directed therapies.

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